T1D occurs in genetically predisposed individuals as a consequence of the progressive, selective destruction of pancreatic beta-cells which is primarily mediated by autoreactive T-cells. The disease process results in loss of insulin secretion and life-long insulin-dependence. At present there is no treatment that fully interdicts islet autoimmunity. Our long-range scientific goals are to understand the natural history of T1D and its molecular basis and implement clinical trials evaluating new strategies to prevent or ameliorate this disease. The objectives of this proposal are twofold: 1) to remain an active participant in the research network. Type 1 Diabetes TrialNet, involved in the design and implementation of new intervention strategies; and 2) to propose a novel intervention strategy with alefacept in individuals with recent onset T1D. Our central hypothesis is that alefacept will have therapeutic value in T1D, and temper the perpetuation of the destructive autoimmune process resulting in T1D, preserving beta-cells and their insulin-secreting capacity. There is a solid rationale for attempting new trials to target memory T cells in T1D: growing evidence links memory T cells with diabetes development, and alefacept specifically targets these cells. It is FDA-approved for the treatment of adult patients with moderate to severe chronic plaque psoriasis, which is also an immune-mediated disease. Importantly, alefacept has an excellent safety profile without the typical side effects of other immunosuppressive agents, which makes it ideally suited for potential chronic treatment of immune-mediated diseases. We propose a phase l/ll double-masked, randomized, placebo-controlled trial to test the hypothesis that alefacept will preserve C-peptide secretion in patients with recent onset T1D. Importantly, there is growing evidence for a role of memory T cells in T1D, and the memory compartment is likely to be enriched in islet-specific autoreactive T cells. We propose two treatment courses during a 1-year period and follow-up for an additional year. The primary metabolic outcome will be stimulated insulin secretion as assessed by C-peptide levels after the mixed meal tolerance test. The primary immunological outcome will be a 50-60% reduction in the frequency of memory T cells during the treatment phases.